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Article ; Online: Analytical Validation of

Debeljak, Marija / Riel, Stacy / Lin, Ming-Tseh / Eshleman, James R / Paller, Channing J

Methods and protocols

2022 Volume 6, Issue 1

Abstract: Manganese superoxide dismutase-2 ( ...

Abstract	Manganese superoxide dismutase-2 (
Language	English
Publishing date	2022-12-31
Publishing country	Switzerland
Document type	Journal Article
ISSN	2409-9279
ISSN (online)	2409-9279
DOI	10.3390/mps6010004
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Article: Islands of genomic stability in the face of genetically unstable metastatic cancer.

Bowland, Kirsten / Lai, Jiaying / Skaist, Alyza / Zhang, Yan / Teh, Selina Shiqing K / Roberts, Nicholas J / Thompson, Elizabeth / Wheelan, Sarah J / Hruban, Ralph H / Karchin, Rachel / Iacobuzio-Donahue, Christine A / Eshleman, James R

bioRxiv : the preprint server for biology

2024

Abstract: Introduction: Metastatic cancer affects millions of people worldwide annually and is the leading cause of cancer-related deaths. Most patients with metastatic disease are not eligible for surgical resection, and current therapeutic regimens have varying ...

Abstract	Introduction: Metastatic cancer affects millions of people worldwide annually and is the leading cause of cancer-related deaths. Most patients with metastatic disease are not eligible for surgical resection, and current therapeutic regimens have varying success rates, some with 5-year survival rates below 5%. Here we test the hypothesis that metastatic cancer can be genetically targeted by exploiting single base substitution mutations unique to individual cells that occur as part of normal aging prior to transformation. These mutations are targetable because ~10% of them form novel tumor-specific "NGG" protospacer adjacent motif (PAM) sites targetable by CRISPR-Cas9. Methods: Whole genome sequencing was performed on five rapid autopsy cases of patient-matched primary tumor, normal and metastatic tissue from pancreatic ductal adenocarcinoma decedents. CRISPR-Cas9 PAM targets were determined by bioinformatic tumor-normal subtraction for each patient and verified in metastatic samples by high-depth capture-based sequencing. Results: We found that 90% of PAM targets were maintained between primary carcinomas and metastases overall. We identified rules that predict PAM loss or retention, where PAMs located in heterozygous regions in the primary tumor can be lost in metastases (private LOH), but PAMs occurring in regions of loss of heterozygosity (LOH) in the primary tumor were universally conserved in metastases. Conclusions: Regions of truncal LOH are strongly retained in the presence of genetic instability, and therefore represent genetic vulnerabilities in pancreatic adenocarcinomas. A CRISPR-based gene therapy approach targeting these regions may be a novel way to genetically target metastatic cancer.
Language	English
Publishing date	2024-01-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.26.577508
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Article ; Online: High-Grade, Nonsarcomatoid Chromophobe Renal Cell Carcinoma: A Series of 22 Cases With Novel Molecular Features on a Subset.

Baraban, Ezra G / Elias, Roy / Lin, Ming-Tseh / Ged, Yasser / Zhu, Jing / Pallavajjala, Aparna / Singla, Nirmish / Lotan, Tamara L / Argani, Pedram / Eshleman, James R / Epstein, Jonathan I

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2024 Volume 37, Issue 5, Page(s) 100472

Abstract: Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma and typically exhibits indolent behavior, though a rare subset can exhibit high-grade morphologic features and is associated with a poor prognosis. Although ...

Abstract	Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma and typically exhibits indolent behavior, though a rare subset can exhibit high-grade morphologic features and is associated with a poor prognosis. Although there are limited data on the molecular characteristics of metastatic and sarcomatoid ChRCC, the molecular features of high-grade, nonsarcomatoid ChRCC remain unexplored. Herein, we characterize 22 cases of ChRCC with high-grade, nonsarcomatoid components. High-grade ChRCC frequently demonstrated advanced stage at diagnosis (64% ≥pT3a or N1), with regions of extrarenal extension, nodal metastases, and vascular invasion consisting solely of high-grade ChRCC morphologically. We performed spatially guided panel-based DNA sequencing on 11 cases comparing high-grade and low-grade regions (n = 22 samples). We identified recurring somatic alterations emblematic of ChRCC, including deletions of chromosomes 1, 2, 6, 10, 13, 17, and 21 in 91% (10/11) of cases and recurring mutations in TP53 (81.8%, n = 9/11) and PTEN (36.4%, n = 4/11). Notably, although PTEN and TP53 alterations were found in both high-grade and low-grade regions, private mutations were identified in 3 cases, indicating convergent evolution. Finally, we identified recurring RB1 mutations in 27% (n = 3) of high-grade regions leading to selective protein loss by immunohistochemistry not observed in adjacent low-grade regions. This finding was confirmed in The Cancer Genome Atlas cohort where 2 of 66 cases contained RB1 mutations and demonstrated unequivocal high-grade, nonsarcomatoid morphology. We also detected multiple chromosomal gains confined to the high-grade regions, consistent with imbalanced chromosome duplication. These findings broaden our understanding of the molecular pathogenesis of ChRCC and suggest that subclonal RB1 mutations can drive the evolution to high-grade, nonsarcomatoid ChRCC.
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1016/j.modpat.2024.100472
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Zs.A 2450: Show issues

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Article ; Online: Using a CA19-9 Tumor Marker Gene Test to Assess Outcome After Pancreatic Cancer Surgery.

Ando, Yohei / Dbouk, Mohamad / Blackford, Amanda L / Yoshida, Takeichi / Saba, Helena / Abou Diwan, Elizabeth / Yoshida, Kanako / Sokoll, Lori / Eshleman, James R / Burkhart, Richard / He, Jin / Goggins, Michael

Annals of surgical oncology

2024 Volume 31, Issue 5, Page(s) 2902–2912

Abstract: Background: Cancer antigen 19-9 (CA19-9) is widely used as a marker of pancreatic cancer tumor burden and response to therapy. Synthesis of CA19-9 and its circulating levels are determined by variants encoding the fucosyltransferases, FUT2 and FUT3. ... ...

Abstract	Background: Cancer antigen 19-9 (CA19-9) is widely used as a marker of pancreatic cancer tumor burden and response to therapy. Synthesis of CA19-9 and its circulating levels are determined by variants encoding the fucosyltransferases, FUT2 and FUT3. Individuals can be grouped into one of four functional FUT groups (FUT3-null, FUT-low, FUT-intermediate, FUT-high), each with its own CA19-9 reference range based on its predicted capacity to produce CA19-9. The authors hypothesized that a FUT variant-based CA19-9 tumor marker gene test could improve the prognostic performance of CA19-9. Methods: Preoperative and pre-treatment CA19-9 levels were measured, and FUT variants were determined in 449 patients who underwent surgery for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2010 and 2020, including 270 patients who underwent neoadjuvant therapy. Factors associated with recurrence-free and overall survival were determined in Cox proportional hazards models. Results: Higher preoperative CA19-9 levels were associated with recurrence and mortality for patients in the higher-FUT groups (FUT-intermediate, FUT-high for mortality, with adjustment for other prognostic factors; hazard ratio [HR], 1.34 and 1.58, respectively; P < 0.001), but not for those in the lower-FUT groups (FUT3-null, FUT-low). As a tumor marker, CA19-9 levels of 100 U/ml or lower after neoadjuvant therapy and normalization of CA19-9 based on FUT group were more sensitive but less specific predictors of evidence for a major pathologic response to therapy (little/no residual tumor) and of early recurrence (within 6 months). Conclusion: Among patients undergoing pancreatic cancer resection, a CA19-9 tumor marker gene test modestly improved the prognostic performance of CA19-9.
MeSH term(s)	Humans ; CA-19-9 Antigen ; Biomarkers, Tumor/genetics ; Retrospective Studies ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/surgery ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/surgery ; Prognosis
Chemical Substances	CA-19-9 Antigen ; Biomarkers, Tumor
Language	English
Publishing date	2024-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1200469-8
ISSN	1534-4681 ; 1068-9265
ISSN (online)	1534-4681
ISSN	1068-9265
DOI	10.1245/s10434-024-14942-5
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Article: Mechanism of delayed cell death following simultaneous CRISPR-Cas9 targeting in pancreatic cancers.

Teh, Selina Shiqing K / Halper-Stromberg, Eitan / Morsberger, Laura / Bennett, Alexis / Bowland, Kirsten / Skaist, Alyza / Cai, Fidel / Liang, Hong / Hruban, Ralph H / Roberts, Nicholas J / Scharpf, Robert B / Zou, Ying S / Eshleman, James R

bioRxiv : the preprint server for biology

2023

Abstract: When we transduced pancreatic cancers with sgRNAs that targeted 2-16 target sites in the human genome, we found that increasing the number of CRISPR-Cas9 target sites produced greater cytotoxicity, with >99% growth inhibition observed by targeting only ... ...

Abstract	When we transduced pancreatic cancers with sgRNAs that targeted 2-16 target sites in the human genome, we found that increasing the number of CRISPR-Cas9 target sites produced greater cytotoxicity, with >99% growth inhibition observed by targeting only 12 sites. However, cell death was delayed by 2-3 weeks after sgRNA transduction, in contrast to the repair of double strand DNA breaks (DSBs) that happened within 3 days after transduction. To explain this discrepancy, we used both cytogenetics and whole genome sequencing to interrogate the genome. We first detected chromatid and chromosome breaks, followed by radial formations, dicentric, ring chromosomes, and other chromosomal aberrations that peaked at 14 days after transduction. Structural variants (SVs) were detected at sites that were directly targeted by CRISPR-Cas9, including SVs generated from two sites that were targeted, but the vast majority of SVs (89.4%) were detected elsewhere in the genome that arose later than those directly targeted. Cells also underwent polyploidization that peaked at day 10 as detected by XY FISH assay, and ultimately died via apoptosis. Overall, we found that the simultaneous DSBs induced by CRISPR-Cas9 in pancreatic cancers caused chromosomal instability and polyploidization that ultimately led to delayed cell death.
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.03.535384
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Article ; Online: MLH1 Loss in Primary Prostate Cancer.

Nourmohammadi Abadchi, Sanaz / Sena, Laura A / Antonarakis, Emmanuel S / Pritchard, Colin C / Eshleman, James R / Konnick, Eric Q / Salipante, Stephen J / Shenderov, Eugene / Lotan, Tamara L

JCO precision oncology

2023 Volume 7, Page(s) e2200611

Abstract: Purpose: Among mismatch repair-deficient (MMRd) prostate cancers, loss of MLH1 is relatively uncommon and few cases have been reported in detail.: Methods: Here, we describe the molecular features of two cases of primary prostate cancer with MLH1 ... ...

Abstract	Purpose: Among mismatch repair-deficient (MMRd) prostate cancers, loss of MLH1 is relatively uncommon and few cases have been reported in detail. Methods: Here, we describe the molecular features of two cases of primary prostate cancer with MLH1 loss detected by immunohistochemistry, and in one case, confirmed via transcriptomic profiling. Results: Both cases were microsatellite stable on standard polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing, but showed evidence of MSI on a newer PCR-based long mononucleotide repeat (LMR) assay and by next-generation sequencing. Germline testing was negative for Lynch syndrome-associated mutations in both cases. Targeted or whole-exome tumor sequencing using multiple commercial/academic platforms (Foundation, Tempus, JHU, and UW-OncoPlex) showed modestly elevated, though variable, tumor mutation burden estimates (2.3-10 mutations/Mb) consistent with MMRd, but without identifiable pathogenic single-nucleotide or indel mutations in Conclusion: These cases highlight the challenges in identifying MLH1-deficient prostate cancers using standard MSI testing and commercial sequencing panels, and support the utility of immunohistochemical assays and LMR- or sequencing-based MSI testing for detection of MMRd prostate cancers.
MeSH term(s)	Male ; Humans ; DNA Methylation/genetics ; Adaptor Proteins, Signal Transducing/genetics ; Nuclear Proteins/genetics ; Microsatellite Instability ; Prostatic Neoplasms/genetics ; MutL Protein Homolog 1/genetics ; MutL Protein Homolog 1/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Nuclear Proteins ; MLH1 protein, human ; MutL Protein Homolog 1 (EC 3.6.1.3)
Language	English
Publishing date	2023-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ISSN	2473-4284
ISSN (online)	2473-4284
DOI	10.1200/PO.22.00611
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Article ; Online: Screening for pancreatic cancer has the potential to save lives, but is it practical?

Mazer, Benjamin L / Lee, Jae W / Roberts, Nicholas J / Chu, Linda C / Lennon, Anne Marie / Klein, Alison P / Eshleman, James R / Fishman, Elliot K / Canto, Marcia Irene / Goggins, Michael G / Hruban, Ralph H

Expert review of gastroenterology & hepatology

2023 Volume 17, Issue 6, Page(s) 555–574

Abstract: Introduction: Most patients with pancreatic cancer present with advanced stage, incurable disease. However, patients with high-grade precancerous lesions and many patients with low-stage disease can be cured with surgery, suggesting that early detection ...

Abstract	Introduction: Most patients with pancreatic cancer present with advanced stage, incurable disease. However, patients with high-grade precancerous lesions and many patients with low-stage disease can be cured with surgery, suggesting that early detection has the potential to improve survival. While serum CA19.9 has been a long-standing biomarker used for pancreatic cancer disease monitoring, its low sensitivity and poor specificity have driven investigators to hunt for better diagnostic markers. Areas covered: This review will cover recent advances in genetics, proteomics, imaging, and artificial intelligence, which offer opportunities for the early detection of curable pancreatic neoplasms. Expert opinion: From exosomes, to circulating tumor DNA, to subtle changes on imaging, we know much more now about the biology and clinical manifestations of early pancreatic neoplasia than we did just five years ago. The overriding challenge, however, remains the development of a practical approach to screen for a relatively rare, but deadly, disease that is often treated with complex surgery. It is our hope that future advances will bring us closer to an effective and financially sound approach for the early detection of pancreatic cancer and its precursors.
MeSH term(s)	Humans ; Artificial Intelligence ; Early Detection of Cancer/methods ; Pancreatic Neoplasms/diagnosis ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/therapy ; Circulating Tumor DNA ; Biomarkers, Tumor/genetics ; Pancreatic Neoplasms
Chemical Substances	Circulating Tumor DNA ; Biomarkers, Tumor
Language	English
Publishing date	2023-07-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2481021-6
ISSN	1747-4132 ; 1747-4124
ISSN (online)	1747-4132
ISSN	1747-4124
DOI	10.1080/17474124.2023.2217354
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Zs.A 6978: Show issues

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Article ; Online: Compact zinc finger architecture utilizing toxin-derived cytidine deaminases for highly efficient base editing in human cells.

Fauser, Friedrich / Kadam, Bhakti N / Arangundy-Franklin, Sebastian / Davis, Jessica E / Vaidya, Vishvesha / Schmidt, Nicola J / Lew, Garrett / Xia, Danny F / Mureli, Rakshaa / Ng, Colman / Zhou, Yuanyue / Scarlott, Nicholas A / Eshleman, Jason / Bendaña, Yuri R / Shivak, David A / Reik, Andreas / Li, Patrick / Davis, Gregory D / Miller, Jeffrey C

Nature communications

2024 Volume 15, Issue 1, Page(s) 1181

Abstract: Nucleobase editors represent an emerging technology that enables precise single-base edits to the genomes of eukaryotic cells. Most nucleobase editors use deaminase domains that act upon single-stranded DNA and require RNA-guided proteins such as Cas9 to ...

Abstract	Nucleobase editors represent an emerging technology that enables precise single-base edits to the genomes of eukaryotic cells. Most nucleobase editors use deaminase domains that act upon single-stranded DNA and require RNA-guided proteins such as Cas9 to unwind the DNA prior to editing. However, the most recent class of base editors utilizes a deaminase domain, DddA
MeSH term(s)	Humans ; Gene Editing ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; DNA/metabolism ; Zinc Fingers ; Cytidine/genetics ; CRISPR-Cas Systems
Chemical Substances	Cytidine Deaminase (EC 3.5.4.5) ; DNA (9007-49-2) ; Cytidine (5CSZ8459RP)
Language	English
Publishing date	2024-02-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45100-w
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Article: Development of novel tools for dissection of central versus peripheral dopamine D

Bonifazi, Alessandro / Ellenberger, Michael / Farino, Zachary J / Aslanoglou, Despoina / Rais, Rana / Pereira, Sandra / Mantilla-Rivas, José O / Boateng, Comfort A / Eshleman, Amy J / Janowsky, Aaron / Hahn, Margaret K / Schwartz, Gary J / Slusher, Barbara S / Newman, Amy Hauck / Freyberg, Zachary

bioRxiv : the preprint server for biology

2024

Abstract: Dopamine (DA) ... ...

Abstract	Dopamine (DA) D
Language	English
Publishing date	2024-02-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.21.581451
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Article ; Online: Using Tumor Marker Gene Variants to Improve the Diagnostic Accuracy of DUPAN-2 and Carbohydrate Antigen 19-9 for Pancreatic Cancer.

Ando, Yohei / Dbouk, Mohamad / Yoshida, Takeichi / Saba, Helena / Abou Diwan, Elizabeth / Yoshida, Kanako / Dbouk, Ali / Blackford, Amanda L / Lin, Ming-Tseh / Lennon, Anne Marie / Burkhart, Richard A / He, Jin / Sokoll, Lori / Eshleman, James R / Canto, Marcia Irene / Goggins, Michael

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2024 , Page(s) JCO2301573

Abstract: Purpose: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, ... ...

Abstract	Purpose: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in Materials and methods: Using a training/validation study design, Results: In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] Conclusion: Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.23.01573
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