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Article ; Online: Next-Generation Sequencing-Based Antigen-Receptor Gene Clonality Assays: Will They Become the Clinical Standard?

Ho, Caleb / Rothberg, Paul G

The Journal of molecular diagnostics : JMD

2021 Volume 23, Issue 9, Page(s) 1043–1046

MeSH term(s)	Gene Rearrangement, T-Lymphocyte/genetics ; Genes, Immunoglobulin ; Genes, T-Cell Receptor ; High-Throughput Nucleotide Sequencing/methods ; High-Throughput Nucleotide Sequencing/standards ; Humans ; Leukemia, B-Cell/genetics ; Molecular Diagnostic Techniques/methods ; Molecular Diagnostic Techniques/standards ; Neoplasm, Residual ; Neoplasms, Plasma Cell/genetics
Language	English
Publishing date	2021-07-20
Publishing country	United States
Document type	Editorial
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2021.07.002
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Article ; Online: Common clonal origin of three distinct hematopoietic neoplasms in a single patient: B-cell lymphoma, T-cell lymphoma, and polycythemia vera.

Nkosi, Dingani / Allbee, Andrew W / Rothberg, Paul G / Friedberg, Jonathan W / Evans, Andrew G

Cold Spring Harbor molecular case studies

2024 Volume 9, Issue 4

Abstract: The potential for more than one distinct hematolymphoid neoplasm to arise from a common mutated stem or precursor cell has been proposed based on findings in primary human malignancies. Particularly, angioimmunoblastic T-cell lymphoma (AITL), which ... ...

Abstract	The potential for more than one distinct hematolymphoid neoplasm to arise from a common mutated stem or precursor cell has been proposed based on findings in primary human malignancies. Particularly, angioimmunoblastic T-cell lymphoma (AITL), which shares a somatic mutation profile in common with other hematopoietic malignancies, has been reported to occur alongside myeloid neoplasms or clonal B-cell proliferations, with identical mutations occurring in more than one cell lineage. Here we report such a case of an elderly woman who was diagnosed over a period of 8 years with diffuse large B-cell lymphoma, polycythemia vera, and AITL, each harboring identical somatic mutations in multiple genes. Overall, at least five identical nucleotide mutations were shared across multiple specimens, with two identical mutations co-occurring at variable variant allele frequencies in all three specimen types. These findings lend credence to the theory that a common mutated stem cell could give rise to multiple neoplasms through parallel hematopoietic differentiation pathways.
MeSH term(s)	Aged ; Female ; Humans ; Polycythemia Vera/genetics ; Lymphoma, T-Cell/genetics ; Hematologic Neoplasms ; Cell Differentiation ; Lymphoma, B-Cell/genetics
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a006313
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Article ; Online: Phenylalanine hydroxylase deficiency treatment and management: A systematic evidence review of the American College of Medical Genetics and Genomics (ACMG).

Adams, April D / Fiesco-Roa, Moisés Ó / Wong, Lawrence / Jenkins, Gabrielle P / Malinowski, Jennifer / Demarest, Olivia M / Rothberg, Paul G / Hobert, Judith A

Genetics in medicine : official journal of the American College of Medical Genetics

2023 Volume 25, Issue 9, Page(s) 100358

Abstract: Purpose: Elevated serum phenylalanine (Phe) levels due to biallelic pathogenic variants in phenylalanine hydroxylase (PAH) may cause neurodevelopmental disorders or birth defects from maternal phenylketonuria. New Phe reduction treatments have been ... ...

Abstract	Purpose: Elevated serum phenylalanine (Phe) levels due to biallelic pathogenic variants in phenylalanine hydroxylase (PAH) may cause neurodevelopmental disorders or birth defects from maternal phenylketonuria. New Phe reduction treatments have been approved in the last decade, but uncertainty on the optimal lifespan goal Phe levels for patients with PAH deficiency remains. Methods: We searched Medline and Embase for evidence of treatment concerning PAH deficiency up to September 28, 2021. Risk of bias was evaluated based on study design. Random-effects meta-analyses were performed to compare IQ, gestational outcomes, and offspring outcomes based on Phe ≤ 360 μmol/L vs > 360 μmol/L and reported as odds ratio and 95% CI. Remaining results were narratively synthesized. Results: A total of 350 studies were included. Risk of bias was moderate. Lower Phe was consistently associated with better outcomes. Achieving Phe ≤ 360 μmol/L before conception substantially lowered the risk of negative effect to offspring in pregnant individuals (odds ratio = 0.07, 95% CI = 0.04-0.14; P < .0001). Adverse events due to pharmacologic treatment were common, but medication reduced Phe levels, enabling dietary liberalization. Conclusions: Reduction of Phe levels to ≤360 μmol/L through diet or medication represents effective interventions to treat PAH deficiency.
MeSH term(s)	Pregnancy ; Female ; Humans ; United States ; Genetics, Medical ; Phenylalanine ; Phenylketonurias/drug therapy ; Phenylketonurias/genetics ; Phenylalanine Hydroxylase/genetics ; Phenylketonuria, Maternal ; Genomics
Chemical Substances	Phenylalanine (47E5O17Y3R) ; Phenylalanine Hydroxylase (EC 1.14.16.1)
Language	English
Publishing date	2023-07-20
Publishing country	United States
Document type	Systematic Review ; Practice Guideline ; Journal Article
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1016/j.gim.2022.12.005
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Article ; Online: Incidental splenic findings in pancreatosplenectomy specimens resected for primary pancreatic lesions.

Patel, Nisha / Evans, Andrew G / Rothberg, Paul G / Gonzalez, Raul S

Histopathology

2019 Volume 75, Issue 5, Page(s) 746–754

Abstract: Aims: Little has been written on the frequency and nature of incidental splenic lesions diagnosed on histopathological examination of pancreatosplenectomy specimens.: Methods and results: For 191 such specimens, incidental histological findings after ...

Abstract	Aims: Little has been written on the frequency and nature of incidental splenic lesions diagnosed on histopathological examination of pancreatosplenectomy specimens. Methods and results: For 191 such specimens, incidental histological findings after haematopathologist re-review were tabulated. Cases suspicious for lymphoid malignancy underwent molecular analysis for immunoglobulin heavy and kappa light chain rearrangement. Follow-up was obtained on selected cases. In five cases (3%), the spleen was sampled but not mentioned in the original microscopic report; all were normal on re-review. Otherwise, most (171 of 186, 92%) were initially diagnosed as normal, with 160 (94%) remaining so on re-review. Findings on re-review not initially described (n = 11, 6%) included four cases with splenic morphology suspicious for possible leukaemia/lymphoma involvement. Additional findings included abscess formation, foamy macrophages, necrotising granulomas and simple cysts. Fifteen spleens were initially diagnosed as abnormal; the histopathological process was confirmed in all, including non-necrotising granulomas, cysts, Gamna-Gandy bodies, foamy macrophages, involvement by pancreatic neoplasm and involvement by known chronic lymphocytic leukaemia (CLL). Molecular analysis was performed on the five cases of known/suspected lymphoma and two were positive for monoclonal gene rearrangement, including the known CLL and a previously undiagnosed case with similar immunophenotype. Conclusions: Incidental splenic findings are not uncommon in pancreatosplenectomy specimens. While most are of limited clinical significance, low-grade lymphoproliferative disorders may go undetected if the spleen is overlooked. We recommend careful observation of splenic findings in these specimens, with a low threshold for haematopathological consultation when in doubt.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Immunophenotyping ; Incidental Findings ; Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Lymphoma/pathology ; Lymphoproliferative Disorders/diagnosis ; Lymphoproliferative Disorders/pathology ; Male ; Middle Aged ; Pancreas/pathology ; Pancreas/surgery ; Pancreatectomy ; Retrospective Studies ; Spleen/pathology ; Spleen/surgery ; Splenic Neoplasms/diagnosis ; Splenic Neoplasms/pathology ; Young Adult
Language	English
Publishing date	2019-09-05
Publishing country	England
Document type	Journal Article
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.13948
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Article ; Online: Clonal cytopenia of undetermined significance (CCUS)-associated reversion of donor-derived, transient αβ T-cell large granular clonal lymphocytosis, emerging post-transplant in a patient with a history of γδ T-cell large granular lymphocytic leukemia.

El Hussein, Siba / Evans, Andrew G / Fitzsimmons, John M / Leong, Nufatt / Buldo, Meghan / Segal, Jeremy P / Jajosky, Audrey N / Rothberg, Paul G / Liesveld, Jane L / Oltvai, Zoltán N

Cold Spring Harbor molecular case studies

2023 Volume 9, Issue 2

Abstract: Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) has revolutionized the therapy of hematolymphoid malignancies. Yet, how to best detect or predict the emergence of HSCT-related complications remain unresolved. Here, we describe a ... ...

Abstract	Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) has revolutionized the therapy of hematolymphoid malignancies. Yet, how to best detect or predict the emergence of HSCT-related complications remain unresolved. Here, we describe a case of donor-derived, transient Alpha Beta (αβ) T-cell large granular clonal lymphocytosis and cytopenia that emerged post-HSCT in a patient with a history of gamma delta (γδ) T-cell large granular lymphocytic leukemia (T-LGLL). Clonal unrelatedness of post-transplant T-LGL lymphocytosis to the patient's pretransplant T-LGLL was first identified by T-cell receptor (TCR) PCR showing different sized fragments of rearranged gamma chains, in addition to shift from γδ to αβ TCR expression by flow cytometry analyses. Donor-derivation of the patient's post-transplant clonal lymphocytosis was confirmed by serial chimerism analyses of recipient's blood specimens demonstrating 100% donor DNA. Moreover, oncogenic
MeSH term(s)	Humans ; Leukemia, Large Granular Lymphocytic/genetics ; Lymphocytosis/genetics ; Core Binding Factor Alpha 2 Subunit ; Clonal Hematopoiesis ; DNA Modification Methylases ; T-Lymphocytes
Chemical Substances	Core Binding Factor Alpha 2 Subunit ; DNA Modification Methylases (EC 2.1.1.-)
Language	English
Publishing date	2023-05-09
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a006241
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Article ; Online: Is Tubulocystic Renal Cell Carcinoma Real?: Genomic Analysis Confirms the World Health Organization Classification.

Ding, Yi / Miyamoto, Hiroshi / Rothberg, Paul G

The Journal of molecular diagnostics : JMD

2017 Volume 20, Issue 1, Page(s) 28–30

Abstract: This commentary highlights the article by Lawrie et al that validates that tubulocystic renal cell carcinoma is a distinct type of renal neoplasm. ...

Abstract	This commentary highlights the article by Lawrie et al that validates that tubulocystic renal cell carcinoma is a distinct type of renal neoplasm.
MeSH term(s)	Carcinoma, Renal Cell/classification ; Carcinoma, Renal Cell/genetics ; Gene Expression Regulation, Neoplastic ; Genomics/methods ; Humans ; Kidney Neoplasms/classification ; Kidney Neoplasms/genetics ; Mutation/genetics ; RNA, Untranslated/genetics ; RNA, Untranslated/metabolism ; World Health Organization
Chemical Substances	RNA, Untranslated
Language	English
Publishing date	2017-11-16
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2017.10.004
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Article: Next-Generation Sequencing for Minimal Residual Disease Surveillance in Acute Lymphoblastic Leukemia: An Update.

Reyes-Barron, Cynthia / Burack, W Richard / Rothberg, Paul G / Ding, Yi

Critical reviews in oncogenesis

2018 Volume 22, Issue 5-6, Page(s) 559–567

Abstract: Monitoring minimal residual disease (MRD) is an important predictor of outcome in acute lymphoblastic leukemia (ALL) and is used in risk stratification, prognosis determination, and therapy guidance. Several laboratory techniques have proven utility for ... ...

Abstract	Monitoring minimal residual disease (MRD) is an important predictor of outcome in acute lymphoblastic leukemia (ALL) and is used in risk stratification, prognosis determination, and therapy guidance. Several laboratory techniques have proven utility for characterizing leukemic cells and following MRD through diagnosis, remission and possible recurrence. Methods for determining MRD are based on the detection of leukemia-specific aberrant immunophenotypes by mulitparameter flow cytometry or the evaluation of leukemia-specific rearranged immunoglobulin or T-cell receptor sequences by quantitative real-time PCR. Next-generation sequencing (NGS) is emerging as a new flexible and sensitive tool to detect MRD, which allows identification of clonal composition and scalable sensitivity depending on sequence coverage. As NGS becomes more accessible and affordable, guidelines should be established for its application to MRD surveillance.
MeSH term(s)	High-Throughput Nucleotide Sequencing ; Humans ; Immunophenotyping ; Neoplasm, Residual/complications ; Neoplasm, Residual/epidemiology ; Neoplasm, Residual/genetics ; Neoplasm, Residual/pathology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Prognosis ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2018-03-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1036388-9
ISSN	0893-9675
ISSN	0893-9675
DOI	10.1615/CritRevOncog.2017020588
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Article: Imatinib: resisting the resistance.

Rothberg, Paul G

Leukemia research

2003 Volume 27, Issue 11, Page(s) 977–978

MeSH term(s)	Antineoplastic Agents/therapeutic use ; Benzamides ; DNA Mutational Analysis/methods ; Drug Resistance, Neoplasm/genetics ; Enzyme Inhibitors ; Humans ; Imatinib Mesylate ; Leukemia/drug therapy ; Piperazines/therapeutic use ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/genetics ; Pyrimidines/therapeutic use
Chemical Substances	Antineoplastic Agents ; Benzamides ; Enzyme Inhibitors ; Piperazines ; Pyrimidines ; Imatinib Mesylate (8A1O1M485B) ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2003-05-27
Publishing country	England
Document type	Comment ; Editorial
ZDB-ID	752396-8
ISSN	1873-5835 ; 0145-2126
ISSN (online)	1873-5835
ISSN	0145-2126
DOI	10.1016/s0145-2126(03)00096-1
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Article ; Online: Mutations of the TERT promoter are common in basal cell carcinoma and squamous cell carcinoma.

Scott, Glynis A / Laughlin, Todd S / Rothberg, Paul G

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

2013 Volume 27, Issue 4, Page(s) 516–523

Abstract: Telomerase is frequently expressed in cancer and contributes to carcinogenesis. Two recent publications report the identification of a set of recurrent mutations in melanoma in the promoter of the telomerase reverse transcriptase gene (TERT) that appears ...

Abstract	Telomerase is frequently expressed in cancer and contributes to carcinogenesis. Two recent publications report the identification of a set of recurrent mutations in melanoma in the promoter of the telomerase reverse transcriptase gene (TERT) that appears to be the result of mutagenesis from ultraviolet (UV) radiation. Both groups reported that the mutations increase the transcription of TERT. This prompted our search for similar mutations in two other UV-related skin cancers, basal cell carcinoma, and squamous cell carcinoma. We found that the activating TERT promoter mutations reported in melanoma are also frequent in squamous cell carcinoma (50%) and basal cell carcinoma, the latter including both sporadic tumors (78%) and tumors from patients with nevoid basal cell carcinoma syndrome (68%). These mutations were found in only 1 of 11 Bowen's disease (squamous cell carcinoma in situ) specimens, and in none of 15 non-malignant skin specimens and 57 blood specimens. The mutations were frequently homozygous or hemizygous, with little or no normal signal at the mutated positions. These data suggest that TERT promoter mutations are the most frequent putative oncogenic mutations in cutaneous cancer.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Bowen's Disease/enzymology ; Bowen's Disease/genetics ; Bowen's Disease/pathology ; Carcinoma, Basal Cell/enzymology ; Carcinoma, Basal Cell/genetics ; Carcinoma, Basal Cell/pathology ; DNA Mutational Analysis ; Female ; Heterozygote ; Homozygote ; Humans ; Male ; Middle Aged ; Mutation ; Promoter Regions, Genetic ; Skin Neoplasms/enzymology ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Telomerase/genetics
Chemical Substances	TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2013-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1038/modpathol.2013.167
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Zs.A 2450: Show issues

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Article ; Online: Pigmented epithelioid melanocytoma (animal-type melanoma): An institutional experience.

Bax, Michael J / Brown, Marc D / Rothberg, Paul G / Laughlin, Todd S / Scott, Glynis A

Journal of the American Academy of Dermatology

2017 Volume 77, Issue 2, Page(s) 328–332

Abstract: Background: Pigmented epithelioid melanocytoma (PEM) is an uncommon, recently described entity with unknown biologic behavior. There is a high rate of regional metastases, but limited evidence of distant metastases or disease-related death.: Objective! ...

Abstract	Background: Pigmented epithelioid melanocytoma (PEM) is an uncommon, recently described entity with unknown biologic behavior. There is a high rate of regional metastases, but limited evidence of distant metastases or disease-related death. Objective: We sought to report our series of patients given a diagnosis of PEM at our institution and provide mutational analysis of genes commonly implicated in melanoma in 2 cases. Methods: The pathology database was queried for cases of PEM diagnosed at the University of Rochester. Charts were reviewed for follow-up information. Mutational analysis of melanoma-associated genes was performed on 2 cases. Results: Nine cases of PEM were retrieved in a 10-year retrospective review. Five patients underwent sentinel lymph node biopsy with 3 of 5 having a positive sentinel lymph node. All 9 patients are alive and disease-free with average follow-up of 38.75 months. Two tumors were tested for common melanoma-associated mutations, and were negative, except for a telomerase reverse transcriptase promoter deletion detected in 1 sample. The deletion has not been associated with melanoma, and therefore its biologic significance is unclear. Limitations: Small sample size, retrospective nature, and single institution experience are limitations. Conclusions: PEM appears to have an indolent behavior. However, currently the evidence is too limited to provide insight into its true biologic potential.
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; DNA Mutational Analysis ; Female ; Humans ; Lymphatic Metastasis ; Male ; Melanoma/genetics ; Melanoma/secondary ; Melanoma/surgery ; Middle Aged ; Neoplasm Staging ; Nevus, Blue/pathology ; Promoter Regions, Genetic ; Retrospective Studies ; Sentinel Lymph Node Biopsy ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Skin Neoplasms/surgery ; Survival Rate ; Telomerase/genetics ; Young Adult
Chemical Substances	Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2017-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	603641-7
ISSN	1097-6787 ; 0190-9622
ISSN (online)	1097-6787
ISSN	0190-9622
DOI	10.1016/j.jaad.2017.01.029
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