Analyses of a patient with 3 sequential Post Transplant Lymphoprolierative Disease (PTLD) biopsies reveal persistence of Histone 1 gene mutation, suspected to mediate PTLD
Bibliographic record
Abstract
Introduction: Post allograft transplant patients are prone to develop a continuum of lympho-proliferative diseases (PTLD) that exhibit distinct clinicopathological forms that range from benign to malignant. The molecular pathogenesis of PTLD is not well established. Methods: We analyzed an unusual case of a 15 year old child who received a lung transplant at age 7 and developed PTLD first in the right tonsil (polymorphic PTLD) 4 months post transplant and then in the left shin and associated lymph node (PTLD-Burkitt Lymphoma) 4 years later. Histopathology and immunohistopathology (IHC) features of the left shin mass were typical for Burkitt Lymphoma with diagnostic features of CD20+, CD10+ve, TdT-ve, EBER+ve, IGH clonal for B cells and Ig-cMyc fusion positve by FISH analysis. The child received chemotherapy and was in remission for 3 years. At 8 years post transplant, he developed an enlargement of the left tonsil. Histopathology and IHC lack evidence of recurrent Burkitt Lymphoma as the B cells are polyclonal, CD10-ve and EBV-ve. FISH was negative for Ig-cMyc fusion. A diagnosis of a polymorphic PTLD was made. With the recently available TruSight RNA Pan-Cancer assay, RNA was extracted from the two most recent tissue samples and NGS libraries were enriched using the 1385 gene panel. Results show the PTLD- Burkitt Lymphoma has additional mutations in the cMyc locus and TP53. The distinctly common mutations notable for Pediatric Burkitt Lymphoma in immunocompetent patients such as ID3, DDX3X, ARID1A and SMARCA4 that are noted in our database and described in a recent publication by B. Burkhardt et al (Nature communication 13:3881;2022) are absent. cMyc, TP53 and all of these mutations are absent in the post chemotherapy polymorphic PTLD in the right tonsil. However, a mutation of Linker Histone 1 (H1-4) gene is detected in the Burkitt PTLD mass and this recurrent polymorphic PTLD tonsil. Conclusions: This result shows there is a persistence of non clonal B cells that are chemotherapy resistant. The patient is currently stable under clinical surveillance. The pathological consequence of H1ST-1(1-4) mutation in the B cells of this patient appears to be supported by a study in a preclinical mouse model that Histone H1 loss drives lymphoma by disrupting 3D chromatin structure (N. Yusufova et. al. Nature 589:299-305; 2021). In this study, knock-in mice carying this mutation alone have prolonged survival as compared with knock-in mice with genetic constructs that contain additional oncogenic driver genes. Based on our findings of the persistence of lymphoid cells with a mutation of gene encoding for a epigenomic gene[HIST-1 (1-4) ], we suspect this mutation plays a role that drives the development of PTLD in this patient. Keywords: Diagnostic and Prognostic Biomarkers, Non-Hodgkin (Pediatric, Adolescent, and Young Adult), Pathology and Classification of Lymphomas No conflicts of interests pertinent to the abstract.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".