Molecular Profiling Reveals Prognostically Significant Subtypes of Canine Lymphoma

Frantz, Aric M.; Sarver, Aaron L.; Ito, Daisuke; Phang, Tzu L.; Karimpour-Fard, Anis; Scott, Milcah C.; Valli, V. E.; Lindblad‐Toh, Kerstin; Burgess, Kristine; Husbands, Brian D; Henson, Michael; Borgatti, Antonella; Kisseberth, William C.; Hunter, Lawrence; Breen, Matthew; O’Brien, Timothy; Modiano, Jaime F.

doi:10.1177/0300985812465325

Cited by 99 publications

(124 citation statements)

References 31 publications

(60 reference statements)

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“…Boxers often develop lymphoblastic T-cell lymphomas as well as peripheral T-cell lymphoma (PTCL) (Lurie et al 2008), both aggressive forms of T-cell lymphoma (Frantz et al 2013), whereas golden retrievers are more prone to developing T-zone lymphomas that are relatively mild and have not been described in humans (Fosmire et al 2007;Seelig et al 2014). The typical mutation pattern in those two breeds is remarkably distinct.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

et al. 2015

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Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B-and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B-and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

et al. 2015

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“…Recognizing the limitations of small sample numbers, there were no obvious differences in clinical presentation or outcome between these 2 histologic subtypes. A recent paper examining gene expression profiles in a small number of canine lymphoma cases suggests that both PTCL and LBT have similar gene expression profiles and may represent a continuum of the same disease 26. Work comparing surface phenotype with the Kiel cytologic classification in a small subset of canine T‐cell lymphomas found that 5/8 small clear cell (T zone correlate) and 5/5 pleomorphic mixed small and large (PTCL correlate) tumors expressed surface CD4 4.…”

Section: Discussionmentioning

confidence: 99%

Flow Cytometric Characterization and Clinical Outcome of CD4+ T‐Cell Lymphoma in Dogs: 67 Cases

Avery

Burton

Bromberek

et al. 2014

Veterinary Internal Medicne

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BackgroundCanine T‐cell lymphoma (TCL) is conventionally considered an aggressive disease, but some forms are histologically and clinically indolent. CD4 TCL is reported to be the most common subtype of TCL. We assessed flow cytometric characteristics, histologic features when available, and clinical outcomes of CD4+ TCL to determine if flow cytometry can be used to subclassify this group of lymphomas.ObjectiveTo test the hypothesis that canine CD4+ T‐cell lymphoma (TCL) is a homogeneous group of lymphomas with an aggressive clinical course.AnimalsSixty‐seven dogs diagnosed with CD4+ TCL by flow cytometry and treated at 1 of 3 oncology referral clinics.MethodsRetrospective multivariable analysis of outcome in canine CD4+ TCL including patient characteristics, treatment, and flow cytometric features.ResultsThe majority of CD4+ TCL were CD45+, expressed low class II MHC, and exhibited an aggressive clinical course independent of treatment regimen (median survival, 159 days). Histologically, CD4+ TCL were classified as lymphoblastic or peripheral T cell. Size of the neoplastic lymphocytes had a modest effect on both PFI and survival in this group. A small number of CD4+ TCL were CD45− and class II MHC high, and exhibited an apparently more indolent clinical course (median survival not yet reached).Conclusions and Clinical ImportanceAlthough the majority of CD4+ TCL in dogs had uniform clinical and flow cytometric features and an aggressive clinical course, a subset had a unique immunophenotype that predicts significantly longer survival. This finding strengthens the utility of flow cytometry to aid in the stratification of canine lymphoma.

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“…First, it is possible that this treatment would be most effective against a specific subset of DLBCL, such as EZH2-mutated GC DLBCL. It has been challenging to separate canine DLBCLs into activated B-cell (ABC) type and GC-type DLBCL 11, 53 , although one study suggested canine DLBCL might be more similar to human ABC type DLBCL 54 . Second, the study was designed to address chemosensitization of LPCs by valspodar, and the sample size was not powered to reveal if this protocol would significantly improve survival outcomes.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…RNA prepared from biopsies obtained at diagnosis (Day 0) and on the fourth day of neoadjuvant treatment for enrolled dogs (Day 4) was quantified and assessed for quality as described 11, 22 . Briefly, total RNA was quantified using a fluorimetric RiboGreen assay and the total RNA integrity was assessed using capillary electrophoresis in the Agilent BioAnalyzer 2100 to generate RNA Integrity Numbers (RIN).…”

Section: Methodsmentioning

confidence: 99%

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A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

et al. 2017

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We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

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Molecular Profiling Reveals Prognostically Significant Subtypes of Canine Lymphoma

Cited by 99 publications

References 31 publications

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

Flow Cytometric Characterization and Clinical Outcome of CD4+ T‐Cell Lymphoma in Dogs: 67 Cases

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

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