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A pluripotency signature predicts histologic transformation and influences survival in follicular lymphoma patients.

ABSTRACT: Histologic transformation (HT) of follicular lymphoma to diffuse large B-cell lymphoma (DLBCL-t) is associated with accelerated disease course and drastically worse outcome, yet the underlying mechanisms are poorly understood. We show that a network of gene transcriptional modules underlies HT. Central to the network hierarchy is a signature strikingly enriched for pluripotency-related genes. These genes are typically expressed in embryonic stem cells (ESCs), including MYC and its direct targets. This core ESC-like program was independent of proliferation/cell-cycle and overlapped but was distinct from normal B-cell transcriptional programs. Furthermore, we show that the ESC program is correlated with transcriptional programs maintaining tumor phenotype in transgenic MYC-driven mouse models of lymphoma. Although our approach was to identify HT mechanisms rather than to derive an optimal survival predictor, a model based on ESC/differentiation programs stratified patient outcomes in 2 independent patient cohorts and was predictive of propensity of follicular lymphoma tumors to transform. Transformation was associated with an expression signature combining high expression of ESC transcriptional programs with reduced expression of stromal programs. Together, these findings suggest a central role for an ESC-like signature in the mechanism of HT and provide new clues for potential therapeutic targets.

SUBMITTER: Gentles AJ

PROVIDER: S-EPMC2759646 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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A pluripotency signature predicts histologic transformation and influences survival in follicular lymphoma patients.

Gentles Andrew J AJ Alizadeh Ash A AA Lee Su-In SI Myklebust June H JH Shachaf Catherine M CM Shahbaba Babak B Levy Ronald R Koller Daphne D Plevritis Sylvia K SK

Blood 20090727 15

Histologic transformation (HT) of follicular lymphoma to diffuse large B-cell lymphoma (DLBCL-t) is associated with accelerated disease course and drastically worse outcome, yet the underlying mechanisms are poorly understood. We show that a network of gene transcriptional modules underlies HT. Central to the network hierarchy is a signature strikingly enriched for pluripotency-related genes. These genes are typically expressed in embryonic stem cells (ESCs), including MYC and its direct targets ...[more]

PMID: 19636063

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Project description:BackgroundFollicular 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 findingsUsing 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.ConclusionsOur 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.

Project description:A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma Pancreatic ductal adenocarcinoma (PDAC), comprising over 90% of all pancreatic cancers, remains a lethal disease with an estimated 232,000 new cases, 227,000 deaths per year worldwide, and a less than 5% five-year survival rate. Currently the standard of care for the 20% of patients with localized disease is surgery followed by chemotherapy, and in some cases radiation. Unfortunately despite the use of adjuvant therapy, median survival remains at best 23 months. It is important to note however, that up to 27% of patients with resected PDAC can survive for five years. However, in these studies examining actual long-term survivors, only two have found that adjuvant therapy was associated with improved survival. In addition, randomized controlled trials of gemcitabine-based chemotherapy demonstrate an improvement in median survival of at best 3 months. One possible conclusion from these studies is that tumor biology dictates outcome and that our current adjuvant therapy has only a modest impact on altering a patient's course.Hypothesizing that the dismal outcome of patients with localized disease is due to the presence of micrometastasic disease, current clinical investigation has focused on preoperative or neoadjuvant therapy. This approach, where patients who cannot tolerate the stress of therapy or develop metastatic disease during treatment are spared surgery, has demonstrated an overall survival of 34 months in this highly selected patient population. Therefore the ability to select patients who would most benefit from a neoadjuvant approach may be important. One way to do this is to define a prognostic gene signature that can identify patients with more aggressive tumor biology upfront. reference x sample The 30 Nebraska and UNC samples were not analyzed with clinical data so it is not provided. One of the PE samples is missing some clinical data.

Dataset Information

A pluripotency signature predicts histologic transformation and influences survival in follicular lymphoma patients.

Publications

A pluripotency signature predicts histologic transformation and influences survival in follicular lymphoma patients.

Similar Datasets

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