Publications by authors named "Antonia R Sepulveda"

81 Publications

Performance of the Abbott ID NOW rapid SARS-CoV-2 amplification assay in relation to nasopharyngeal viral RNA loads.

J Clin Virol 2021 07 24;140:104843. Epub 2021 Apr 24.

Department of Pathology, George Washington University School of Medicine and Health Sciences, United State; Department of Pathology and Laboratory Medicine, George Washington University Hospital, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jcv.2021.104843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091002PMC
July 2021

Invasive carcinoma versus pseudoinvasion: interobserver variability in the assessment of left-sided colorectal polypectomies.

J Clin Pathol 2021 Apr 12. Epub 2021 Apr 12.

Department of Pathology and Cell Biology, Columbia University Medical Center, New York City, New York, USA.

Objectives: Misplaced epithelium in adenomas can occasionally be difficult to distinguish from invasive adenocarcinoma. We evaluated interobserver variability in the assessment of left-sided colon polypectomies for pseudoinvasion versus invasive adenocarcinoma and further investigated relevant histological findings.

Methods: 28 consecutive left-sided colon polyps with the keywords "pseudoinvasion", "epithelial misplacement", "herniation", "prolapse" or "invasive adenocarcinoma" were collected from 28 patients and reviewed by eight gastrointestinal pathologists. Participants assessed stromal hemosiderin, lamina propria/eosinophils surrounding glands, desmoplasia, high grade dysplasia/intramucosal adenocarcinoma and margin status and rendered a diagnosis of pseudoinvasion, invasive adenocarcinoma, or both.

Results: Agreement among pathologists was substantial for desmoplasia (κ=0.70), high grade dysplasia/intramucosal adenocarcinoma (κ=0.66), invasive adenocarcinoma (κ=0.63) and adenocarcinoma at the margin (κ=0.65). There was moderate agreement for hemosiderin in stroma (κ=0.53) and prolapse/pseudoinvasion (κ=0.50). Agreement was low for lamina propria/eosinophils around glands (κ=0.12). For invasive adenocarcinoma, seven or more pathologists agreed in 24 of 28 cases (86%), and there was perfect agreement in 19/28 cases (68%). For pseudoinvasion, seven or more pathologists agreed in 19 of 28 cases (68%), and there was perfect agreement in 16/28 cases (57%).

Conclusion: Moderate to substantial, though imperfect, agreement was achieved in the distinction of pseudoinvasion from invasive carcinoma.
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http://dx.doi.org/10.1136/jclinpath-2021-207406DOI Listing
April 2021

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

Gastroenterology 2020 08 20;159(2):575-590. Epub 2020 Apr 20.

Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Background & Aims: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis.

Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5 (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB.

Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5 cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5 cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5 cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation.

Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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http://dx.doi.org/10.1053/j.gastro.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484392PMC
August 2020

Defining current gaps in quality measures for cancer immunotherapy: consensus report from the Society for Immunotherapy of Cancer (SITC) 2019 Quality Summit.

J Immunother Cancer 2020 01;8(1)

Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA

Background: Quality measures are important because they can help improve and standardize the delivery of cancer care among healthcare providers and across tumor types. In an environment characterized by a rapidly shifting immunotherapeutic landscape and lack of associated long-term outcome data, defining quality measures for cancer immunotherapy is a high priority yet fraught with many challenges.

Methods: Thus, the Society for Immunotherapy of Cancer convened a multistakeholder expert panel to, , identify the current gaps in measures of quality cancer care delivery as it relates to immunotherapy and to, , advance priority concepts surrounding quality measures that could be developed and broadly adopted by the field.

Results: After reviewing the existing quality measure landscape employed for immunotherapeutic-based cancer care, the expert panel identified four relevant National Quality Strategy domains (patient safety, person and family-centered care, care coordination and communication, appropriate treatment selection) with significant gaps in immunotherapy-based quality cancer care delivery. Furthermore, these domains offer opportunities for the development of quality measures as they relate to cancer immunotherapy. These four quality measure concepts are presented in this consensus statement.

Conclusions: This work represents a first step toward defining and standardizing quality delivery of cancer immunotherapy in order to realize its optimal application and benefit for patients.
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http://dx.doi.org/10.1136/jitc-2019-000112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057483PMC
January 2020

Downregulation of () follows the stepwise progression to gastric adenocarcinoma.

Oncotarget 2019 Jun 11;10(39):3852-3864. Epub 2019 Jun 11.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.

Gastric adenocarcinoma (GC) is a leading cause of cancer-related deaths worldwide. The transcription factor gene () is methylated and downregulated in human GC tissues. Using human GC samples, we determined which cells downregulate , when downregulation occurs, if downregulation correlates with clinical-pathologic characteristics, and whether plays a role in invasion and/or proliferation of cultured cells. We analyzed stomach tissues from 98 patients [8 normal mucosa, 8 intestinal metaplasia (IM), 7 dysplasia, 91 GC] by immunohistochemistry for FLI1. Epithelial cells from normal, IM, and low-grade dysplasia (LGD) showed strong nuclear FLI1 staining. GC epithelial cells showed significantly less nuclear FLI1 staining as compared to normal epithelium, IM and LGD (P=1.2×10, P=1.4×10 and P=0.006, respectively). expression did not correlate with tumor stage or differentiation, but was associated with patient survival, depending on tumor differentiation. We tested the functional role of FLI1 by assaying proliferation and invasion in cultured GC cells. Lentiviral-transduced overexpression in GC AGS cells inhibited invasion by 73.5% (P = 0.001) and proliferation by 31.5% (P = 0.002), as compared to controls. Our results support a combined role for FLI1 as a suppressor of invasiveness and proliferation in gastric adenocarcinoma, specifically in the transition from pre-cancer lesions and dysplasia to invasive adenocarcinoma, and suggest that FLI1 may be a prognostic biomarker of survival in gastric cancers.
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http://dx.doi.org/10.18632/oncotarget.26974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570468PMC
June 2019

Testing algorithm for identification of patients with TRK fusion cancer.

J Clin Pathol 2019 Jul 9;72(7):460-467. Epub 2019 May 9.

Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, New York, USA.

The neurotrophic tyrosine receptor kinase () gene family encodes three tropomyosin receptor kinases (TRKA, TRKB, TRKC) that contribute to central and peripheral nervous system development and function. gene fusions are oncogenic drivers of various adult and paediatric tumours. Several methods have been used to detect gene fusions including immunohistochemistry, fluorescence in situ hybridisation, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing. For patients with TRK fusion cancer, TRK inhibition is an important therapeutic target. Following the FDA approval of the selective TRK inhibitor, larotrectinib, as well as the ongoing development of multi-kinase inhibitors with activity in TRK fusion cancer, testing for gene fusions should become part of the standard diagnostic process. In this review we discuss the biology of gene fusions, and we present a testing algorithm to aid detection of these gene fusions in clinical practice and guide treatment decisions.
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http://dx.doi.org/10.1136/jclinpath-2018-205679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589488PMC
July 2019

High-resolution genomic alterations in Barrett's metaplasia of patients who progress to esophageal dysplasia and adenocarcinoma.

Int J Cancer 2019 11 2;145(10):2754-2766. Epub 2019 May 2.

Department of Pathology and Cell Biology, Columbia University Irving Medical Center (CUIMC), New York, NY.

The main risk factor for esophageal dysplasia and adenocarcinoma (DAC) is Barrett's esophagus (BE), characterized by intestinal metaplasia. The critical genomic mechanisms that lead to progression of nondysplastic BE to DAC remain poorly understood and require analyses of longitudinal patient cohorts and high-resolution assays. We tested BE tissues from 74 patients, including 42 nonprogressors from two separate groups of 21 patients each and 32 progressors (16 in a longitudinal cohort before DAC/preprogression-BE and 16 with temporally concurrent but spatially separate DAC/concurrent-BE). We interrogated genome-wide somatic copy number alterations (SCNAs) at the exon level with high-resolution SNP arrays in DNA from formalin-fixed samples histologically confirmed as nondysplastic BE. The most frequent abnormalities were SCNAs involving FHIT exon 5, CDKN2A/B or both in 88% longitudinal BE progressors to DAC vs. 24% in both nonprogressor groups (p = 0.0004). Deletions in other genomic regions were found in 56% of preprogression-BE but only in one nonprogressor-BE (p = 0.0004). SCNAs involving FHIT exon 5 and CDKN2A/B were also frequently detected in BE temporally concurrent with DAC. TP53 losses were detected in concurrent-BE but not earlier in preprogression-BE tissues of patients who developed DAC. CDKN2A/p16 immunohistochemistry showed significant loss of expression in BE of progressors vs. nonprogressors, supporting the genomic data. Our data suggest a role for CDKN2A/B and FHIT in early progression of BE to dysplasia and adenocarcinoma that warrants future mechanistic research. Alterations in CDKN2A/B and FHIT by high-resolution assays may serve as biomarkers of increased risk of progression to DAC when detected in BE tissues.
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http://dx.doi.org/10.1002/ijc.32351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750991PMC
November 2019

Experimental microdissection enables functional harmonisation of pancreatic cancer subtypes.

Gut 2019 06 18;68(6):1034-1043. Epub 2019 Jan 18.

Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA.

Objective: Pancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has attempts at expression-based molecular classification. The goal of this work is to profile purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples.

Design: We used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts.

Results: Our analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes.

Conclusion: Our findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.
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http://dx.doi.org/10.1136/gutjnl-2018-317706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509007PMC
June 2019

Utilization Rate of Helicobacter pylori Immunohistochemistry Is Not Associated With the Diagnostic Rate of Helicobacter pylori Infection.

Appl Immunohistochem Mol Morphol 2019 10;27(9):694-698

Department of Pathology and Cell Biology.

Background: Utilization rates of immunohistochemistry (IHC) for the diagnosis of Helicobacter pylori infection may vary by laboratory and/or pathologists. IHC for H. pylori is not performed routinely in our practice. Instead, it is used in selected cases at the pathologists' discretion (and according to their specific criteria). The purpose of this study was to determine if IHC utilization rates correlated with rates of detecting H. pylori infection.

Materials And Methods: We searched our records and investigated all gastric biopsies for 1 calendar year. H. pylori diagnostic rate and IHC utilization rate was calculated for each pathologist.

Results: Overall, the rate of diagnosis was 12.1% and the IHC utilization rate was 45.2%. Individual pathologists had H. pylori diagnostic rates ranging from 3.6% to 34.1% (median: 11.1%) and IHC utilization ranging from 17.1% to 95.2% (median: 42.2%). The rate of detection of H. pylori infection among pathologists showed no significant correlation with rates of IHC utilization (Pearson coefficient=0.121).

Conclusions: Increasing use of IHC is not independently associated with the diagnostic rate of infection. Ultimately, if we assume that the case mix was similar for each pathologist, it suggests that more liberal criteria to order IHC does not result in more infections diagnosed.
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http://dx.doi.org/10.1097/PAI.0000000000000680DOI Listing
October 2019

A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors.

Nat Genet 2018 07 18;50(7):979-989. Epub 2018 Jun 18.

Department of Pathology, Columbia University, New York, NY, USA.

We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
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http://dx.doi.org/10.1038/s41588-018-0138-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421579PMC
July 2018

CXCR4-expressing progenitors in the gastric antrum contribute to gastric cancer development.

Oncotarget 2017 Dec 10;8(67):111012-111025. Epub 2017 Nov 10.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.

was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express . The relevance of expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using -CreERT mice, we revealed that antral cells, distinct from the population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above or CCK2R cells. antral progenitors can serve as an origin of antral tumors induced by loss of Apc or MNU treatment. antral progenitors, as well as other antral stem/progenitor population, express Cxcr4, and are located in close proximity to Cxcl12 (the Cxcr4 ligand)-expressing endothelium. During antral carcinogenesis, there is an expansion of Cxcr4 epithelial cells as well as the Cxcl12 perivascular niche. Deletion of Cxcl12 in endothelial cells or pharmacological blockade of Cxcr4 inhibits antral tumor growth. Cxcl12/Cxcr4 signaling may be a potential therapeutic target.
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http://dx.doi.org/10.18632/oncotarget.22451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762301PMC
December 2017

Is a Potential Target for Diagnostic PET/CT Imaging in Barrett's Dysplasia and Esophageal Adenocarcinoma.

Clin Cancer Res 2018 03 5;24(5):1048-1061. Epub 2017 Dec 5.

II. Medizinische Klinik, Technische Universitat München, Munich, Germany.

Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma. Here we utilized an transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis. IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4 columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. In conclusion, the recruitment of CXCR4 immune cells and expansion of CXCR4 epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1756DOI Listing
March 2018

AGA White Paper: Optimizing Endoscopic Ultrasound-Guided Tissue Acquisition and Future Directions.

Clin Gastroenterol Hepatol 2018 03 23;16(3):318-327. Epub 2017 Oct 23.

Division of Gastroenterology and Hepatology, Ochsner Medical Center, New Orleans, Louisiana.

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http://dx.doi.org/10.1016/j.cgh.2017.10.020DOI Listing
March 2018

Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus.

Nature 2017 10 12;550(7677):529-533. Epub 2017 Oct 12.

Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.

In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63KRT5KRT7) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63KRT5KRT7 basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.
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http://dx.doi.org/10.1038/nature24269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831195PMC
October 2017

HER2 Heterogeneity in Gastroesophageal Cancer Detected by Testing Biopsy and Resection Specimens.

Arch Pathol Lab Med 2018 Apr 7;142(4):516-522. Epub 2017 Aug 7.

From the Department of Pathology and Cell Biology, Columbia University Medical Center, New York Presbyterian Hospital, New York.

Context: - In advanced gastric, esophageal, and gastroesophageal junction adenocarcinomas (GE-GEJ-AC) that overexpress ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2), anti-HER2 monoclonal antibody therapy confers survival benefit. To select patients for treatment, HER2 expression and gene amplification are evaluated by immunohistochemistry (IHC) and in situ hybridization.

Objective: - To determine whether GE-GEJ-AC tested for HER2 on biopsy specimens of a primary tumor show different IHC scores and/or HER2 amplification by in situ hybridization in matched resection specimens, potentially changing therapy eligibility.

Design: - Immunohistochemistry and silver in situ hybridization were performed in biopsy and/or resection specimens from 100 patients. HER2 testing was performed in matched resection and biopsy specimens of 15 cases to determine whether GE-GEJ-AC with IHC scores of 0, 1, and 2 in biopsy and resection specimens had different IHC and silver in situ hybridization results.

Results: - The IHC 3 cases showed HER2 amplification in 4 of 5 cases (80%), and IHC scores of 0, 1, and 2 showed 3.5%, 14.3%, and 23.5% HER2 amplification by silver in situ hybridization. Among the 15 paired biopsy and resection specimens, 9 (60%) had at least pT2 stage GE-GEJ-AC with HER2 IHC scores of 0, 1, or 2 in the biopsy, and 2 of those 9 cases (22%) had IHC 3 and HER2 amplification by silver in situ hybridization on the resection specimen.

Conclusions: - Our data suggest that HER2 testing should be repeated on resection specimens of GE-GEJ-AC with HER2 IHC scores of negative (0 and 1) or equivocal (2) and in situ hybridization amplification negative biopsy specimen results to evaluate for HER2 heterogeneity when patients are being considered for anti-HER2 therapy.
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http://dx.doi.org/10.5858/arpa.2017-0039-OADOI Listing
April 2018

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline Summary From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.

J Oncol Pract 2017 05 28;13(5):333-337. Epub 2017 Mar 28.

Columbia University, New York; Roswell Park Cancer Institute, Buffalo, NY; University of Texas MD Anderson Cancer Center, Houston; Castle Biosciences, Friendswood, TX; University of Florida Medical Center, Gainesville, FL; University of California Los Angeles Medical Center, Los Angeles; Biocept, San Diego, CA; University of Nebraska Medical Center, Omaha, NE; University of North Carolina School of Medicine, Chapel Hill, NC; University of Colorado Denver School of Medicine, Denver, CO; Mayo Clinic, Scottsdale, AZ; Mayo Clinic, Rochester, MN; Case Western Reserve University, Cleveland, OH; American Society for Clinical Pathology, Washington, DC; College of American Pathologists, Northfield, IL; American Society of Clinical Oncology, Alexandria, VA; and Association for Molecular Pathology, Bethesda, MD.

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http://dx.doi.org/10.1200/JOP.2017.022152DOI Listing
May 2017

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.

J Mol Diagn 2017 03 6;19(2):187-225. Epub 2017 Feb 6.

Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY.

Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens.

Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted.

Results: Twenty-one guideline statements were established.

Conclusions: Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented. Key Words: Molecular diagnostics; Gastrointestinal; Histology; Genetics; Oncology.
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http://dx.doi.org/10.1016/j.jmoldx.2016.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971222PMC
March 2017

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology.

J Clin Oncol 2017 May 6;35(13):1453-1486. Epub 2017 Feb 6.

Antonia R. Sepulveda, Columbia University, New York, NY; Stanley R. Hamilton, Scott E. Kopetz, and Bruce D. Minsky, University of Texas MD Anderson Cancer Center, Houston, TX; Carmen J. Allegra, University of Florida Medical Center, Gainesville, FL; Wayne Grody, UCLA Medical Center, Los Angeles, CA; Allison M. Cushman-Vokoun, University of Nebraska Medical Center, Omaha, NE; William K. Funkhouser, University of North Carolina School of Medicine, Chapel Hill, NC; Christopher Lieu, University of Colorado Denver School of Medicine, Denver, CO; Noralane M. Lindor, Mayo Clinic, Scottsdale, AZ; Federico A. Monzon, Castle Biosciences, Friendswood, TX; Daniel J. Sargent, Mayo Clinic, Rochester, MN; Veena M. Singh, Biocept, San Diego, CA; Joseph Willis, Case Western Reserve University, Cleveland, OH; Jennifer Clark, American Society for Clinical Pathology, Washington, DC; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield, IL; R. Bryan Rumble, American Society of Clinical Oncology, Alexandria, VA; Robyn Temple-Smolkin, Association for Molecular Pathology, Bethesda, MD; and Jan A. Nowak, Roswell Park Cancer Institute, Buffalo, NY.

Purpose Molecular testing of colorectal cancers (CRCs) to improve patient care and outcomes of targeted and conventional therapies has been the center of many recent studies, including clinical trials. Evidence-based recommendations for the molecular testing of CRC tissues to guide epidermal growth factor receptor (EGFR) -targeted therapies and conventional chemotherapy regimens are warranted in clinical practice. The purpose of this guideline is to develop evidence-based recommendations to help establish standard molecular biomarker testing for CRC through a systematic review of the literature. Methods The American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for patients with CRC. A comprehensive literature search that included over 4,000 articles was conducted to gather data to inform this guideline. Results Twenty-one guideline statements (eight recommendations, 10 expert consensus opinions and three no recommendations) were established. Recommendations Evidence supports mutational testing for genes in the EGFR signaling pathway, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize molecular testing for predictive and prognostic molecular biomarkers involve selection of assays, type of specimens to be tested, timing of ordering of tests and turnaround time for testing results. Additional information is available at: www.asco.org/CRC-markers-guideline and www.asco.org/guidelineswiki.
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http://dx.doi.org/10.1200/JCO.2016.71.9807DOI Listing
May 2017

Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology.

Arch Pathol Lab Med 2017 May 6;141(5):625-657. Epub 2017 Feb 6.

From the 1 Department of Pathology and Cell Biology, Columbia University, New York, NY.

Objectives: - To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens.

Methods: - The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted.

Results: - Twenty-one guideline statements were established.

Conclusions: - Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.
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http://dx.doi.org/10.5858/arpa.2016-0554-CPDOI Listing
May 2017

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

Oesophageal adenocarcinoma and gastric cancer: should we mind the gap?

Nat Rev Cancer 2016 04;16(5):305-18

Division of Digestive and Liver Diseases and Herbert Irving Cancer Research Center, Columbia University College of Physicians and Surgeons, 1130 St Nicholas Avenue, New York, New York 10032, USA.

Over recent decades we have witnessed a shift in the anatomical distribution of gastric cancer (GC), which increasingly originates from the proximal stomach near the junction with the oesophagus. In parallel, there has been a dramatic rise in the incidence of oesophageal adenocarcinoma (OAC) in the lower oesophagus, which is associated with antecedent Barrett oesophagus (BO). In this context, there has been uncertainty regarding the characterization of adenocarcinomas spanning the area from the lower oesophagus to the distal stomach. Most relevant to this discussion is the distinction, if any, between OAC and intestinal-type GC of the proximal stomach. It is therefore timely to review our current understanding of OAC and intestinal-type GC, integrating advances from cell-of-origin studies and comprehensive genomic alteration analyses, ultimately enabling better insight into the relationship between these two cancers.
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http://dx.doi.org/10.1038/nrc.2016.24DOI Listing
April 2016

Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis.

Diagn Pathol 2016 Mar 9;11:27. Epub 2016 Mar 9.

Department of Pathology and Cell Biology, Columbia University Medical Center, 630 W 168th Street, VC14-238, New York, NY, 10032, USA.

Background: Four subtypes of hepatocellular adenomas (HCA) are recognized: hepatocyte-nuclear-factor-1α mutated (H-HCA), β-catenin-mutated type with upregulation of glutamine synthetase (b-HCA), inflammatory type (IHCA) with serum-amyloid-A overexpression, and unclassified type. Subtyping may be useful since b-HCA appear to have higher risk of malignant transformation. We sought to apply subtype analysis and assess histological atypia, correlating these with next-generation sequencing analysis.

Methods: Twenty-six HCA were stained with serum amyloid A (SAA), liver fatty acid-binding protein (LFABP), glutamine synthetase (GS), and β-catenin IHC, followed by analysis with a targeted multiplex sequencing panel.

Results: By IHC, 4 HCA (15.4 %) were classified as b-HCA, 11 (42.3 %) as IHCA, 9 (34.6 %) as H-HCA, and two (7.7 %) unclassifiable. Eight HCA (30.8 %) showed atypia (3 b-HCA, 4 IHCA and 1 H-HCA). Targeted sequencing confirmed HNF1A mutations in all H-HCA, confirming reliability of LFABP IHC in identifying these lesions. CTNNB1 mutations were detected in 1 of 4 (25 %) of GS/β-catenin-positive cases, suggesting that positive GS stain does not always correlate with CTNNB1 mutations.

Conclusions: Immunohistochemistry does not consistently identify b-HCA. Mutational analysis improves the diagnostic accuracy of β-catenin-mutated HCA and is an important tool to assess risk of malignancy in HCA.
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http://dx.doi.org/10.1186/s13000-016-0475-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784347PMC
March 2016

High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing.

Mod Pathol 2016 Feb 15;29(2):182-93. Epub 2016 Jan 15.

Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.

Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.
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http://dx.doi.org/10.1038/modpathol.2015.144DOI Listing
February 2016

Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche.

Cancer Cell 2015 Dec 12;28(6):800-814. Epub 2015 Nov 12.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address:

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.
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http://dx.doi.org/10.1016/j.ccell.2015.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684751PMC
December 2015

Mutational analysis by next generation sequencing of gastric type dysplasia occurring in hyperplastic polyps of the stomach: Mutations in gastric hyperplastic polyps.

Exp Mol Pathol 2015 Dec 29;99(3):468-73. Epub 2015 Aug 29.

Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States.

Unlabelled: Gastric hyperplastic polyps (GHP) are the most common type of polyps occurring in the stomach. Although GHP are broadly interpreted as benign lesions, they may progress to dysplasia and adenocarcinoma.

Objective: In this study, we aimed to identify genomic mutations that characterize and may drive malignant transformation in GHP by using next-generation sequencing. Eight GHP (2 with dysplasia, 1 indefinite for dysplasia and 5 without dysplasia) were studied. Only large polyps (>1cm) with gastric differentiation were included in this study, while adenomatous polyps (intestinal-type) were excluded. Immunohistochemistry for MUC2, MUC5A, MUC6, CDX2, p53, and Ki67 was performed. DNA was extracted from formalin-fixed paraffin-embedded sections and sequenced for the detection of somatic mutations. Multiplex sequencing was done with the TrueSeq Amplicon Cancer Panel in the MiSeq platform. Variant annotation and visualization were performed using NextGENe (SoftGenetics) software. No pathogenic mutations were detected in GHP without dysplasia. TP53 gene mutations were the most common alteration in dysplastic GHP (2 of 2 dysplastic cases). PIK3CA mutation was identified in a GHP with pyloric-type dysplasia, whereas foveolar-type dysplasia carried TP53 mutations. In conclusion, TP53 gene mutations are a common alteration in the early dysplastic stage during malignant transformation of GHP. GHP with dysplasia may show dual differentiation. In our study, pyloric-type dysplasia was associated with a PIK3CA alteration whereas foveolar dysplasia carried TP53 mutations. The identification of carcinoma-associated mutations in large GHP provides additional evidence of their neoplastic potential and emphasizes the need for their complete resection and follow-up.
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http://dx.doi.org/10.1016/j.yexmp.2015.08.014DOI Listing
December 2015

Multiple Gastrointestinal Polyps in Patients Treated with BRAF Inhibitors.

Clin Cancer Res 2015 Dec 22;21(23):5215-21. Epub 2015 Jul 22.

Department of Pathology and Cell Biology, Columbia University, New York, New York.

Purpose: BRAF inhibitors (BRAFi) extend survival in BRAF-mutant melanoma but can promote the growth of Ras-mutant neoplasms. This study determined if gastrointestinal polyps found in BRAFi-treated patients harbored Ras mutations.

Experimental Design: Colonic and gastric polyps were identified and resected from BRAFi-treated melanoma patients. Next-generation sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min(+/-) mice. MAPK and β-catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps.

Results: Fourteen patients treated with BRAFi underwent endoscopy to assess for polyps. Seven out of 7 patients >40 years of age and treated for >2 years were found to have colonic tubular adenomas with 4 out of the 7 patients having 5 or more polyps. One patient presented with bleeding from hyperplastic gastric polyps that recurred 6 months after BRAFi rechallenge. NGS performed on polyps found no mutations in MAPK pathway genes, but found APC mutations in all tubular adenomas. A significant increase in the number of polyps was observed in BRAFi-treated compared with control-treated Apc Min(+/-) mice (20.8 ± 9.2 vs 12.8 ± 0.1; P = 0.016). No polyps were observed in BRAFi-treated wild-type mice.

Conclusions: BRAFi may increase the risk of developing hyperplastic gastric polyps and colonic adenomatous polyps. Due to the risk of gastrointestinal bleeding and the possibility of malignant transformation, further studies are needed to determine whether or not endoscopic surveillance should be recommended for patients treated with BRAFi.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668213PMC
December 2015

Evaluation of Mutational Testing of Preneoplastic Barrett's Mucosa by Next-Generation Sequencing of Formalin-Fixed, Paraffin-Embedded Endoscopic Samples for Detection of Concurrent Dysplasia and Adenocarcinoma in Barrett's Esophagus.

J Mol Diagn 2015 Jul 8;17(4):412-9. Epub 2015 Jun 8.

Department of Pathology and Cell Biology, Columbia University, New York City, New York. Electronic address:

Barrett's intestinal metaplasia (BIM) may harbor genomic mutations before the histologic appearance of dysplasia and cancer and requires frequent surveillance. We explored next-generation sequencing to detect mutations with the analytical sensitivity required to predict concurrent high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus by testing nonneoplastic BIM. Formalin-fixed, paraffin-embedded (FFPE) routine biopsy or endoscopic mucosal resection samples from 32 patients were tested: nonprogressors to HGD or EAC (BIM-NP) with BIM, who never had a diagnosis of dysplasia or EAC (N = 13); progressors to HGD or EAC (BIM-P) with BIM and a worse diagnosis of HGD or EAC (N = 15); and four BIM-negative samples. No mutations were detected in the BIM-NP (0 of 13) or BIM-negative samples, whereas the BIM-P samples had mutations in 6 (75%) of 8 cases in TP53, APC, and CDKN2A (P = 0.0005), detected in samples with as low as 20% BIM. We found that next-generation sequencing from routine FFPE nonneoplastic Barrett's esophagus samples can detect multiple mutations in minute areas of BIM with high analytical sensitivity. Next-generation sequencing panels for detection of TP53 and possibly combined mutations in other genes, such as APC and CDKN2A, may be useful in the clinical setting to improve dysplasia and cancer surveillance in patients with Barrett's esophagus.
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http://dx.doi.org/10.1016/j.jmoldx.2015.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484205PMC
July 2015

Molecular and histologic considerations in the assessment of serrated polyps.

Arch Pathol Lab Med 2015 Jun;139(6):730-41

From the Department of Pathology and Cell Biology, Columbia University, New York, New York.

Unlabelled: CONTEXT : Colorectal cancer is a heterogeneous disease resulting from different molecular pathways of carcinogenesis. Recent data evaluating the histologic features and molecular basis of the serrated polyp-carcinoma pathway have significantly contributed to more comprehensive classifications of and treatment recommendations for these tumors.

Objective: To integrate the most recent molecular findings in the context of histologic classifications of serrated lesions and their implications in diagnostic pathology and colorectal cancer surveillance.

Data Sources: Published literature focused on serrated polyps and their association with colorectal cancer.

Conclusions: Three types of serrated polyps are currently recognized: hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas. The BRAF V600E mutation is one of the most frequent molecular abnormalities identified in hyperplastic polyps and sessile serrated adenomas. In contrast, in traditional serrated adenomas, either BRAF V600E or KRAS mutations can be frequently identified. CpG methylation has emerged as a critical molecular mechanism in the sessile serrated pathway. CpG methylation of MLH1 often leads to reduced or lost expression in dysplastic foci and carcinomas arising in sessile serrated adenomas/polyps.
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http://dx.doi.org/10.5858/arpa.2014-0424-RADOI Listing
June 2015

New Insights into the Genetics of Fetal Megacystis: ACTG2 Mutations, Encoding γ-2 Smooth Muscle Actin in Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (Berdon Syndrome).

Fetal Diagn Ther 2015 13;38(4):296-306. Epub 2015 May 13.

Department of Pediatrics, Columbia University Medical Center, New York, N.Y., USA.

Objective: To identify the molecular basis for prenatally suspected cases of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) (MIM 249210) in 3 independent families with clinical and radiographic evidence of MMIHS.

Methods: Whole-exome sequencing (WES) and Sanger sequencing of the ACTG2 gene.

Results: We identified a novel heterozygous de novo missense variant in ACTG2 c.770G>A (p.Arg257His) encoding x03B3;-2 smooth muscle actin (ACTG2) in 2 siblings with MMIHS, suggesting gonadal mosaicism of one of the parents. Two additional de novo missense variants (p.Arg257Cys and p.Arg178His) in ACTG2 were identified in 2 additional MMHIS patients. All of our patients had evidence of fetal megacystis and a normal or slightly increased amniotic fluid volume. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. ACTG2 immunostaining of the intestinal tissue showed an altered muscularis propria, a markedly thinned longitudinal muscle layer, and a reduced amount and abnormal distribution of ACTG2.

Conclusion: Our study demonstrates that de novo mutations in ACTG2 are a cause of fetal megacystis in MMIHS and that gonadal mosaicism may be present in a subset of cases. These findings have implications for the counseling of families with a diagnosis of fetal megacystis with a preserved amniotic fluid volume and associated gastrointestinal findings.
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http://dx.doi.org/10.1159/000381638DOI Listing
October 2016
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