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      Glycolytic biomarkers predict transformation in patients with follicular lymphoma

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          Abstract

          Follicular lymphoma (FL) is an indolent neoplasia comprising approximately 20% of lymphomas. FL is generally considered incurable, with a median survival exceeding 10 years. A subset of FL patients experiences histological transformation (HT) to a more aggressive lymphoma, resulting in markedly poorer clinical outcome, with a reduced median survival after transformation of 1–2 years. Early, reliable prediction of HT would be valuable in the clinical setting, allowing pre-emptive therapeutic intervention. We previously used proteomics to identify the glycolytic enzymes fructose-bisphosphate aldolase A (aldolase A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as candidate predictors of FL transformation. Now, we use immunohistochemistry to evaluate expression of these enzymes in paired primary FLs from patients with (n = 41) or without subsequent HT (n = 49), to test their value as predictive biomarkers. At initial FL diagnosis, patients with subsequent HT had significantly higher expression of aldolase A and GAPDH (p<0.001 and p<0.01) compared with patients without HT. Furthermore, high expression of aldolase A and GAPDH was associated with significantly shorter transformation free survival (p = 0.018, p = 0.001). These data suggest that high expression of aldolase A and GAPDH, may indicate increased metabolic turnover, and that these enzymes may be useful biomarkers in primary FL for predicting the risk of subsequent lymphoma transformation.

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          Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review).

          Jie Zheng (2012)
          Metabolic activities in normal cells rely primarily on mitochondrial oxidative phosphorylation (OXPHOS) to generate ATP for energy. Unlike in normal cells, glycolysis is enhanced and OXPHOS capacity is reduced in various cancer cells. It has long been believed that the glycolytic phenotype in cancer is due to a permanent impairment of mitochondrial OXPHOS, as proposed by Otto Warburg. This view is challenged by recent investigations which find that the function of mitochondrial OXPHOS in most cancers is intact. Aerobic glycolysis in many cancers is the combined result of various factors such as oncogenes, tumor suppressors, a hypoxic microenvironment, mtDNA mutations, genetic background and others. Understanding the features and complexity of the cancer energy metabolism will help to develop new approaches in early diagnosis and effectively target therapy of cancer.
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            Pathogenesis of follicular lymphoma.

            Robert Kridel, L Sehn, Randy Gascoyne (2012)
            The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.
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              Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

              Robert Kridel, Fong Chun Chan, Anja Mottok … (2016)
              Background Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Methods and Findings Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. Conclusions Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
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                Author and article information

                Contributors
                Ida Monrad: Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Charlotte Madsen: Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Kristina Lystlund Lauridsen: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Bent Honoré: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Trine Lindhardt Plesner: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Stephen Hamilton-Dutoit: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Francesco d’Amore: Role: ConceptualizationRole: Writing – review & editing
                Maja Ludvigsen:
                ORCID: http://orcid.org/0000-0001-5089-3271
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Jung Weon Lee: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 22 May 2020
                Publication date Collection: 2020
                Volume: 15
                Issue: 5
                Electronic Location Identifier: e0233449
                Affiliations
                [1 ] Department of Hematology, Aarhus University Hospital, Aarhus, DK
                [2 ] Department of Pathology, Aarhus University Hospital, Aarhus, DK
                [3 ] Department of Biomedicine, Aarhus University, Aarhus, DK
                [4 ] Department of Pathology, Copenhagen University Hospital, Copenhagen, DK
                [5 ] Department of Clinical Medicine, Aarhus University, Aarhus, DK
                Seoul National University College of Pharmacy, REPUBLIC OF KOREA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-5089-3271
                Article
                Publisher ID: PONE-D-20-04605
                DOI: 10.1371/journal.pone.0233449
                PMC ID: 7244150
                PubMed ID: 32442224
                SO-VID: fa53261f-48c8-4fab-8a17-d34a58a0d92f
                Copyright © © 2020 Monrad et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 17 February 2020
                Date accepted : 5 May 2020
                Page count
                Figures: 2, Tables: 1, Pages: 10
                Funding
                This study was funded by the Danish Lymphoma Group (IM), donation from Peter and Alice Madsen (ML), The Merchant Einer Willumsen Memorial Foundation (ML) and the Central Denmark Region (IM).
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Cancer Detection and Diagnosis
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Detection and Diagnosis
                Subject: Research and Analysis Methods
                Subject: Histochemistry and Cytochemistry Techniques
                Subject: Immunohistochemistry Techniques
                Subject: Research and Analysis Methods
                Subject: Immunologic Techniques
                Subject: Immunohistochemistry Techniques
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Biomarkers
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Histology
                Subject: Medicine and Health Sciences
                Subject: Anatomy
                Subject: Histology
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Hematologic Cancers and Related Disorders
                Subject: Lymphomas
                Subject: Medicine and Health Sciences
                Subject: Hematology
                Subject: Hematologic Cancers and Related Disorders
                Subject: Lymphomas
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Metabolism
                Subject: Carbohydrate Metabolism
                Subject: Glucose Metabolism
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Physiology
                Subject: Cell Metabolism
                Custom metadata
                Data Availability All relevant data are within the paper.

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